ACTIVATION OF HISTONE DEACETYLASE 1 (HDAC1) PROTECTS AGAINST DNA DAMAGE AND INCREASES NEURONAL SURVIVAL

• US 20100075926A1
• Filed: 07/23/2009
• Published: 03/25/2010
• Est. Priority Date: 07/23/2008
• Status: Abandoned Application

• Current Assignee: Dohoon Kim, Li-Huei Tsai, Stephen J. Haggarty
• Original Assignee: Dohoon Kim, Li-Huei Tsai, Stephen J. Haggarty
• Inventors: Kim, Dohoon, Haggarty, Stephen J., Tsai, Li-Huei
• Application Number:
  US12/508,481
• Publication Number:
  US 20100075926A1
• Time in Patent Office: Days
• US Class Current: 514/82
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 311/30 not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 311/80 Dibenzopyrans; Hydrogenated dibenzopyrans
• CPC Class Codes: C07D 493/18 Bridged systems

Abstract

The invention provides methods and compounds for the treatment of neurological disorders, including Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, ALS (Amyotrophic Lateral Sclerosis), traumatic brain injury, ischemic brain injury or a stroke. In one aspect the compounds are HDAC1 activators. Exemplary HDAC1 activators include metal chelators, iron chelators, deferoxamin, flavonoids, compounds comprising a catechol moity, ginkgetin K, Chembridge 5104434, sciadopilysin, tetrahydrogamboic acid, TAM-11, LY 235959, CGS 19755, SK&F 97541, etidronic acid, levonordefrin, methyldopa, ampicillin trihydrate, D-aspartic acid, gamma-D-glutamylaminomethylsulfonic acid, phenazopyridine to hydrochloride, oxalamine citrate salt, podophyllotoxin, SK&F 97541, (+-)-4-amino-3-(5-chloro-2-thienyl)-butanoic acid, (RS)-(tetrazol-5-yl) glycine, R(+)-SKF-81297, gambogic acid, and derivatives thereof.

Claims

1. A method for treating a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of an HDAC1 (Histone deacetylase 1) activator to treat the neurological disorder.

2. The method of claim 1, wherein the neurological disorder is Alzheimer'"'"'s disease.

3. The method of claim 1, wherein the neurological disorder is Parkinson'"'"'s disease.

4. The method of claim 1, wherein the neurological disorder is Huntington'"'"'s disease.

5. The method of claim 1, wherein the neurological disorder is ALS (Amyotrophic Lateral Sclerosis).

6. The method of claim 1, wherein the neurological disorder is traumatic brain injury.

7. The method of claim 1, wherein the neurological disorder is ischemic brain injury.

8. The method of claim 1, wherein the HDAC1 activator is an iron chelator.

9. The method of claim 8, wherein the iron chelator is deferoxamine.

10. The method of claim 1, wherein the HDAC1 activator is a flavonoid.

11. The method of claim 10, wherein the flavonoid is ginkgetin K.

12. The method of claim 1, wherein the HDAC1 activator is Chembridge 5104434.

13. The method of claim 1, wherein the HDAC1 activator is gambogic acid.

14. The method of claim 1, wherein the HDAC1 activator is sciadopilysin.

15. The method of claim 1, wherein the HDAC1 activator is tetrahydrogamboic acid.

16. The method of claim 1, wherein the HDAC1 activator is TAM-11.

17. The method of claim 1, wherein the HDAC1 activator is of the formula:

18. The method of claim 1, wherein the HDAC1 activator is a catechol-containing compound of the formula:

19. The method of claim 18, wherein the HDAC1 activator is selected from the group consisting of levonordefrin

20. The method of claim 1, wherein the HDAC1 activator is of the formula:

wherein

21. The method of claim 20, wherein the HDAC1 activator is selected from the group consisting of LY 235959

22. The method of claim 1, wherein the HDAC1 activator is of the formula:

23. The method of claim 1, wherein the HDAC1 activator is of the formula:

24. The method of claim 1, wherein the HDAC1 activator is of the formula:

25. The method of claim 1, wherein the HDAC1 activator is of the formula:

26. A method for protecting a subject against neuronal damage, the method comprising administering to a subject in need of protection against neuronal damage a therapeutically effective amount of an HDAC1 (Histone deacetylase 1) activator to protect against neuronal damage.

27. The method of claim 26, wherein the neuronal damage is ischemic brain damage.

28. The method of claim 26, wherein the neuronal damage is stroke.

29-46. -46. (canceled)

47. A method for increasing HDAC1 (Histone deacetylase 1) activity in a cell, the method comprising contacting the cell with an HDAC1 activator.

48. The method of claim 47, wherein increasing HDAC1 activity comprises increasing the deacetylase activity of HDAC1.

49. The method of claim 47, wherein increasing the HDAC1 activity comprises increasing the expression level of HDAC1.

50. The method of claim 47, wherein the cell is in a subject.

51-68. -68. (canceled)

69. A compound of the formula:

70. A compound of the formula:

71. The compound of claim 70, wherein the HDAC1 activator is selected from the group consisting of levonordefrin

72. A compound of the formula:

73. The compound of claim 72, wherein the HDAC1 activator is selected from the group consisting of LY 235959

74. A compound of the formula:

75. A compound of the formula:

76. A compound of the formula:

77. A compound of the formula:

78-95. -95. (canceled)